One of the most debilitating neurological complications of HIV infection is painful peripheral neuropathy (PPN) associated with nucleoside reverse transcriptase inhibitors (NRTIs). The predominant symptom, excruciating and unremitting pain, is resistant to traditional pharmacological treatment and can interfere with quality of life. Recently, we made the novel observation that several patients with NRTI-induced PPN enrolled in an exercise clinical trial reported less pain and spent more time on treadmill after starting the program. We developed a mouse model of NRTI-induced allodynia to examine the mechanisms underlying drug-evoked allodynia and the analgesic effects of exercise. The drug-treated mice developed profound allodynia that was significantly reduced by just six days of voluntary wheel running. Since Brain-Derived Neurotrophic Factor (BDNF) expression is altered in response to both nerve injury and exercise, it is an ideal candidate to modulate both the drug-induced allodynia and the protective effects of exercise. We hypothesize that a nerve injury-mediated increase in BDNF expression in the spinal dorsal horn (SDH) promotes hyperalgesia by activating N-methyl-D-aspartate receptors (NMDARs) that participate in activity- dependent windup of nociceptive neurons. Further increasing BDNF expression above nerve injury levels in the SDH via aerobic exercise leads to a significant downregulation of the BDNF receptor tropomyosin-related kinase B (trkB.FL) and abrogation of NMDAR activation, producing analgesia. In support of this hypothesis, we demonstrate that intrathecal administration of exogenous BDNF at a dose that has been shown to downregulate trkB.FL abrogates NRTI-induced alloydnia and we have evidence to suggest that trkB.FL phosphorylation is significantly reduced in the SDH of exercised mice. Moreover, animals that lack the dominant negative inhibitor of trkB.FL, trkB.TI, do not develop NRTI-induced allodynia, presumably due to chronic exposure of dorsal horn neurons to high BDNF levels. Thus, we propose that BDNF signaling acts as a "volume control" mechanism in the SDH to modulate the development and persistence of nociception induced by NRTIs, and we will explore this in detail in this proposal. Lay language: A common problem for people with HIV is severe pain in the legs caused by their medications, and pain medicine doesn't help. This study may help us understand this type of pain better so that we can find better ways to reduce pain.